Recognizing that regulatory T cells (Tregs) plays crucial roles in transplant tolerance and high peripheral blood Tregs associated with stable kidney graft function, knowing which volatile anesthetic agents can induce peripheral blood Tregs increment would have clinical implications. This study aimed to compare effects of desflurane and sevoflurane anesthesia on peripheral blood Tregs induction in patients undergoing living donor kidney transplantation.
Trang 1R E S E A R C H A R T I C L E Open Access
Effects of Desflurane and Sevoflurane
anesthesia on regulatory T cells in patients
undergoing living donor kidney
transplantation: a randomized intervention
trial
Arpa Chutipongtanate1, Sasichol Prukviwat1, Nutkridta Pongsakul2, Supanart Srisala3, Nakarin Kamanee1,
Nuttapon Arpornsujaritkun4, Goragoch Gesprasert4, Nopporn Apiwattanakul5, Suradej Hongeng6,
Wichai Ittichaikulthol1, Vasant Sumethkul7and Somchai Chutipongtanate2,8*
Abstract
Background: Volatile anesthetic agents used during surgery have immunomodulatory effects which could affect
postoperative outcomes Recognizing that regulatory T cells (Tregs) plays crucial roles in transplant tolerance and high peripheral blood Tregs associated with stable kidney graft function, knowing which volatile anesthetic agents can induce peripheral blood Tregs increment would have clinical implications This study aimed to compare effects of desflurane and sevoflurane anesthesia on peripheral blood Tregs induction in patients undergoing living donor kidney transplantation Methods: A prospective, randomized, double-blind trial in living donor kidney transplant recipients was conducted at a single center, tertiary-care, academic university hospital in Thailand during August 2015– June 2017 Sixty-six patients were assessed for eligibility and 40 patients who fulfilled the study requirement were equally randomized and allocated
to desflurane versus sevoflurane anesthesia during transplant surgery The primary outcome included absolute changes of peripheral blood CD4+CD25+FoxP3+Tregs which measured by flow cytometry and expressed as the percentage of the total population of CD4+T lymphocytes at pre-exposure (0-h) and post-exposure (2-h and 24-h) to anesthetic gas.P-value
< 0.05 denoted statistical significance
(Continued on next page)
© The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the
* Correspondence: schuti.rama@gmail.com ; somchai.chu@mahidol.edu
2
Pediatric Translational Research Unit, Department of Pediatrics, Faculty of
Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
8 Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine
Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
Full list of author information is available at the end of the article
Trang 2(Continued from previous page)
Results: Demographic data were comparable between groups No statistical difference of peripheral blood Tregs
between desflurane and sevoflurane groups observed at the baseline pre-exposure (3.6 ± 0.4% vs 3.1 ± 0.4%;p = 0.371) and 2-h post-exposure (3.0 ± 0.3% vs 3.5 ± 0.4%;p = 0.319) At 24-h post-exposure, peripheral blood Tregs was
significantly higher in desflurane group (5.8 ± 0.5% vs 4.1 ± 0.3%;p = 0.008) Within group analysis showed patients
receiving desflurane, but not sevoflurane, had 2.7% increase in peripheral blood Treg over 24-h period (p < 0.001)
Conclusion: This study provides the clinical trial-based evidence that desflurane induced peripheral blood Tregs
increment after 24-h exposure, which could be beneficial in the context of kidney transplantation Mechanisms of action and clinical advantages of desflurane anesthesia based on Treg immunomodulation should be investigated in the future Trial registration: ClinicalTrials.gov,NCT02559297 Registered 22 September 2015 - retrospectively registered
Keywords: Clinical trial, Inhalation agent, Kidney transplant, Tregs, Volatile anesthesia
Background
Kidney transplantation is the best option for renal
replace-ment therapy in patients with end-stage renal disease
(ESRD), often restoring quality of life in ESRD patients
Allograft rejection, an immune-mediated process, is a
common cause of transplant failure [1–4] Evidence
indi-cates CD4+CD25+FoxP3+cells, commonly known as
regu-latory T cells (Tregs), play a critical role in preventing
graft rejection by suppression of recipient alloimmune
re-sponse [5–8] In healthy subjects, Tregs represent up to
5% of peripheral CD4+T cells [9–11] In kidney transplant
patients, high peripheral blood Tregs were associated with
stable graft function Low peripheral blood Tregs was
as-sociated with allograft rejection [12–17]
Currently, adoptive transfer of ex vivo expanded Tregs
is a promising strategy to induce transplant tolerance and
control graft rejection in kidney transplant recipients [18,
19] It has been investigated for safety and feasibility in
phase I trials, i.e., the ONE (NCT02091232) and TRACT
(NCT02145325) Identifying Treg-friendly agents from
pharmacologic choices in multiple steps of kidney
trans-plant management may also offer an attractive therapeutic
strategy [19] Characterization of Tregs under various
treatment conditions may help refine current preventive
measures or identify novel therapeutic targets
Volatile anesthetic agents are widely used for general
anesthesia during kidney transplantation A growing
body of evidence from ex vivo and clinical studies [20–
26] suggest desflurane and sevoflurane (halogenated
ether inhaled agents) exhibit immunomodulatory effects
(e.g., cell proliferation, activation, migration, cytokine
production) on neutrophils, macrophages, natural killer
cells, B and T lymphocytes These effects may be
medi-ated via activation of volatile anesthetic receptors (i.e.,
γ-aminobutyric acid type A receptor, nicotinic
acetylcho-line receptor, serotonin receptor and non-canonical
β2-integrins) or via binding to surface adhesion molecules
such as integrin leukocyte function associated antigen-1,
which express differentially on peripheral blood
leuko-cytes [25, 26] However, effects of desflurane and
sevoflurane on Treg immunomodulation is surprisingly overlooked and has only rarely been investigated A bet-ter understanding of these effects would have transla-tional potential For example, the early Treg immunomodulation by anesthetic agents may help miti-gating the initiation of alloimmune responses during the 24-h perioperative period, and works in conjunction with the standard immunosuppressive regimen to seam-lessly maintain the graft survival in LDKT patients This interventional trial aims to compare the immuno-modulatory effects of desflurane and sevoflurane anesthesia on peripheral blood Treg induction in pa-tients undergoing living donor kidney transplantation (LDKT) Several plasma cytokines were measured as the surrogate outcomes of the volatile anesthetic effects on anti- and pro-inflammatory responses Evidence from this study would support future investigation of volatile anesthetic agents as part of perioperative management with an aim to improve transplant outcomes
Methods
Trial design and patient enrollment
This prospective, double-blind, randomized interven-tion trial was approved by the Ethical Clearance Committee on Human Rights Related to Research In-volving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University (protocol
ID 045823) and the protocol was registered to Clini-calTrials.gov (identifier NCT02559297) on September
22, 2015 Patients aged ≥18 years old who received their first living donor kidney transplantation at Ramathibodi Hospital were included in the study Pa-tients were excluded for hyperacute graft rejection, currently on immunosuppressive drugs due to under-lying diseases, receiving blood products during 24-h perioperative period, or patient refusal to participate
in the study at any time point Informed consent was obtained from all subjects No interim analysis was performed during the trial This study followed the CONSORT reporting guideline [27]
Trang 3Randomization was generated in a 1:1 allocation with a
block size of 8 and the random number was put in a
sealed envelope Patients were randomly assigned to
ei-ther desflurane or sevoflurane intervention by drawing a
sealed envelope Randomization took place on the day of
surgery just prior to initiation of anesthesia
Blinding
Subjects and outcome assessors (including laboratory
tech-nicians and all investigators except the designated research
coordinator) were blinded to group allocation throughout
surgery, laboratory investigation and data collection
Blind-ing was uncovered at the time of data analysis
Interventions
Patients were randomly assigned to receive desflurane or
sevoflurane for the maintenance phase of anesthesia In
addition to the randomized inhalation agents, patients
received the same regimen of 1–2 mg of midazolam for
premedication and intravenous anesthetic agents
includ-ing 1–2 mcg kg− 1of fentanyl, 1–2 mg kg− 1of propofol
and 0.5–0.6 mg kg − 1 of atracurium for induction of
anesthesia and intubation A balance anesthesia
tech-nique was used for maintenance phase The inhalation
agent (sevoflurane or desflurane) was used in
conjunc-tion with 50% nitrous oxide in oxygen Ventilaconjunc-tion was
adjusted to maintain normocarbia End-tidal anesthetic
gas monitoring was used to ensure 1.0–1.5 minimum
al-veolar concentration (MAC) of the inhalation agent
dur-ing maintenance phase in both groups
During anesthesia, blood pressure, heart rate, oxygen
saturation, ETCO2, and temperature were monitored
and recorded Blood pressure was maintained within
20% of baseline values Hypotension was managed by
intravenous fluid and ephedrine IV bolus as needed
Total doses of intravenous medications were recorded
All patients in both interventions were transferred to the
kidney transplant unit for postoperative care
Blood sample collection
Venipuncture was performed at three time-points;
pre-exposure (0-h) and post-pre-exposure (2-h, and 24-h) to
in-halation agents Two tubes of 0.5-ml EDTA blood were
collected at each time point, one for Treg enumeration
and the other for cytokine measurement
Outcome measures
The primary outcome was the absolute change in
num-ber of peripheral blood CD4+CD25+FoxP3+Tregs, which
was measured by flow cytometry and expressed as the
percentage of the total population of CD4+ T
lympho-cytes at pre-exposure (0-h) and post-exposure (2-h and
24-h) to anesthetic gas A secondary outcome was the
plasma level of anti-inflammatory cytokine IL-10 (the major cytokine produced by Tregs), TGF-β1 (anti-in-flammatory cytokines produced by many types of cells and required for Tregs differentiation), and pro-inflammatory cytokines produced by T helper (Th) 1/ Th2, i.e., GM-CSF, IFN-ɣ, IL-2, IL-4, IL-5, IL-12, IL-13 and TNF-α, which measured by multiplex immunoassay All measurements were performed in triplicate
Treg enumeration by flow cytometry
Peripheral blood mononuclear cells (PBMC) were iso-lated by density gradient centrifugation Approximately
5 × 105cells were suspended in 20μL phosphate buffer saline (PBS) in the presence of cell surface marker anti-bodies (APC-CD4, PE-Cy7-CD25) (#MHCD0404, #25– 0259-41; ThermoFisher, Florence, KY), mixed well and incubated at room temperature for 15 min Thereafter, cells were permeabilized and intracellularly stained using FoxP3-FITC antibody (#11–4776-42; ThermoFisher) Flow cytometry (BD FACSVerse with BD FACSuite soft-ware; BD Bioscience, San Jose, CA) was used to measure the number of Tregs, expressed as a percentage of CD4+CD25+FoxP3+T cells among the CD4+cell popula-tion The estimated number of CD4 + cells and Treg were calculated by determining the ratio of CD4 + cell count and CD4 + CD25 + FoxP3 + cell count, respect-ively, to the total count in the flow cytometry, and then multiplied by the number of white blood cells measured from the complete blood count (CBC) which ordered at the pre-operative and post-operative evaluations
Cytokine measurement by multiplex immunoassay
Multiplex cytokine immunoassay was performed by BioPlex-200 system (Bio-Rad, Hercules, CA) GM-CSF, IFN-ɣ, IL-2, IL-4, IL-5, IL-10, IL-12, IL13, and TNF-α were detected by BioPlex Pro human cytokine Th1/Th2 assay (Bio-Rad), and TGF-β1 was measured by single-plex custom assay (Bio-Rad) as the manufacturer’s instruction
Sample size estimation and statistical analysis
There was no data related to sevoflurane and desflurane anesthesia on Treg immunomodulation available at the initiation of the study Nevertheless, Pirbudak Cocelli L
et al [21], showed that sevoflurane and desflurane anesthesia caused a significant difference in total lymphocyte count at 2-h post-induction in patients undergoing abdominal surgery Since Treg is a subset of lymphocytes, our study then adopted mean difference and standard deviation to calculate the effect size The nQuery Advisor program was applied for sample size calculation Accordingly, at least 40 patients (20 patients per group) were required to determine statistically sig-nificant mean difference between groups (the effect size
of 0.915, alpha = 0.05 and power = 80%)
Trang 4Statistical analysis was performed by Excel and R
pack-ages Data were reported in number, percentage, mean ±
SD (or SEM) or median [IQR] as appropriate Parametric
and non-parametric tests were used, as appropriate, to
determine difference between groups ANOVA with
Tukey post-hoc test was performed for multiple
com-parison P-value < 0.05 was considered to be statistically
significant
Results
Baseline characteristics
Figure1shows the flow of the participants in this study
A total of 66 patients were assessed for eligibility and 46
patients who met inclusion criteria were recruited
dur-ing August 10, 2015 to June 3, 2017 for randomization
and allocation to the intervention Six patients who met
exclusion criteria after allocation due to receiving
peri-operative blood products were excluded Table1 shows
demographic and clinical data for the 40 patients
en-rolled in this study Most variables, including recipient
factors, donor factors, protocol immunosuppressive
regi-mens, intraoperative parameters, the dosage of
intraven-ous anesthesia were not significantly different between
the intervention groups Donor age and the estimated
blood loss were slightly lower in patients receiving
des-flurane anesthesia Factors contributing to
ischemic-reperfusion injury, i.e., cold and warm ischemic time, were comparable between groups Also, anesthesia time was not different between groups (279 ± 42 min vs
303 ± 45 min, p = 0.098) Given that the depth of sevo-flurane and dessevo-flurane anesthesia was maintained at 1.0–1.5 MAC for each arm, this finding supported that patients were exposed to inhalation agents equally (Table1)
Effects of Desflurane and Sevoflurane anesthesia on Tregs
in LDKT recipients
Figure 2a demonstrates the gating strategy of flow cy-tometry and Fig.2b shows the effects of sevoflurane and desflurane anesthesia on CD4+CD25+FoxP3+ Tregs in peripheral blood of LDKT recipients (n = 20 per group)
No significant difference of peripheral blood Tregs (mean ± SEM) was observed at pre-exposure (3.6 ± 0.4%
vs 3.1 ± 0.4%; p = 0.371) and 2-h post-exposure (3.0 ± 0.3% vs 3.5 ± 0.4%; p = 0.319) between desflurane and sevoflurane, respectively However, at 24-h post-exposure, desflurane group had significantly higher per-ipheral blood Tregs as compared to sevoflurane group (5.8 ± 0.5% vs 4.1 ± 0.3%; p = 0.008) (Fig 2b) Within-group analysis showed that the patients receiving des-flurane had 2.7% increase in Tregs over 24-h period (p <
Fig 1 Flow diagram of study participants
Trang 50.001) (Fig 2b), while this effect was not observed in
sevoflurane group
Although peripheral blood Treg are commonly presented
in the literatures as the percentage of CD25+FoxP3+cells in
the CD4+cell population, one argument was that the
incre-ment in Treg percentage might be corresponding to the
global changes of leukocytes or CD4+T cells in response of surgical procedure and postoperative inflammation but not the influence of inhalation agents To address this issue, the absolute number of white blood cells (as measured by the complete blood count), and the calculated numbers of CD4+ T cells and CD4+CD25+FoxP3+Tregs (details in the
Table 1 Demographic data of LDKT recipients enrolled into the study If not indicated otherwise: n (%)
Recipient
Donor
Protocol immunosuppressive drug
Intraoperative variable
Intravenous anesthesia
Abbreviations: ADPKD Autosomal dominant polycystic kidney disease, BMI Body mass index, HLA Human leukocyte antigen, PRA Panel reactive antibodies
Trang 6Method section), were shown in Fig 2c Postoperative
leukocytosis was observed in both groups as expected (Fig
2c, the left panel), while the number of CD4+ T cells were
not significantly changed during 24-h perioperative period
(Fig 2c, the center panel) Consistently, the number of
Tregs (median [IQR]) were comparable between groups at
the baseline (7 [6,11] vs 8 [4,9] cells/mm3;p = 0.780) and
were significantly higher in desflurane group (12 [9,16] vs
8 [4,12] cells/mm3;p = 0.033) at 24-h post-exposure (Fig
2c, the right panel) This finding suggested the effect of
des-flurane anesthesia on the peripheral blood Treg induction
during 24-h postoperative period
Plasma cytokine levels were measured by multiplex
im-munoassay as a surrogate outcome of immunomodulation
possibly influenced by inhalation agents (n = 26, 12
sevo-flurane and 14 dessevo-flurane) Although there was no
statisti-cally significant difference between groups in any
cytokine, a trend of increased IL-10 was observed in
des-flurane group as compared to sevodes-flurane group at 24-h
post-exposure (27.5 [17.6, 34.4] vs 17.8 [11.4, 22.3] pg/
mL;p = 0.12) (Fig 3 and Supplementary Table1) IL-10,
the signature anti-inflammatory cytokine produced by
Tregs, had an upward trend (1.67-time increased at 24-h
as compared to the baseline pre-exposure) in the patients
receiving desflurane, whereas other cytokines seemed to
be unchanged over the 24-h period (Fig 3 and Supple-mentary Table 1) The transient drop of measured cyto-kines at 2-h was potentially associated with intraoperative factors, e.g., intravenous fluid administration, but not dir-ectly influenced by inhalation agents
An increased trend of plasma IL-10 in the desflurane group was in line with previous results (Fig 2) and sug-gested that desflurane anesthesia was associated with IL-10-producing Tregs induction in LDKT patients during the perioperative period Matched-pair data of Tregs and plasma IL-10 levels in 26 patients (14 desflurane, 12 sevoflurane) were analyzed to observe this immunophenotypic response Scatter plot showed a positive relationship between Tregs and IL-10 fold changes over 24-h period (Fig.4a), in which the proportion of patients with increased Tregs and IL-10 immunophenotypic response was higher in the desflurane group (Fig 4b) Taken together, our findings revealed that desflurane anesthesia induced IL-10-producing Tregs in LDKT recipients over 24-h postoperative period
Discussion
Increasing evidence suggests that volatile anesthetic agents exhibit immunomodulatory effects linked to innate and
Fig 2 Effects of desflurane and sevoflurane anesthesia on the CD4 + CD25 + FoxP3+ Tregs ( n = 20 per group) a Representative gating strategy of Treg enumeration b The percentage of Treg in the CD4 + cell population c The absolute number of white blood cells (left), and the calculated numbers of CD4 + cells (center) and Treg (right), in peripheral blood (details in the Method section) The result showed that the LDKT patients who received desflurane anesthesia, but not sevoflurane, had significantly increased Tregs in the peripheral blood at 24-h post-exposure All experiments were performed in triplicate Des, desflurane; NS, not significant; Sevo, sevoflurane
Trang 7adaptive immunity via induction and suppression of
neu-trophils, macrophages, NK cells and B and T lymphocytes
[25,26] However, their effects on Treg have remained
un-known This study, for the first time, showed that
desflur-ane, but not sevoflurdesflur-ane, increased Treg frequency in
peripheral blood of LDKT recipients during 24-h
peri-operative period Selection of desflurane anesthesia in
kid-ney transplantation may have additional benefits to kidkid-ney
graft outcome, particularly preventing allograft rejection
Studies showed that kidney transplant patients who
maintained a high level of peripheral blood Tregs were
associated with better outcomes [14, 15, 28] San
Segundo D, et al [14], reported that among 90 kidney
transplant recipients, patients who maintained high
levels (above 70th percentile) of peripheral blood Tregs
at both 6 and 12 months had a better prognosis in the
aspect of long-term graft survival after 4 and 5 years
follow-up Liu L, et al [15], compared peripheral blood
Treg levels between 42 patients with stable kidney graft
function and ten patients who suffered from chronic
rejection The results showed that Treg levels were sig-nificantly higher in the stable group than the chronic re-jection group Alberu J, et al [28], investigated the association between Treg levels and de novo donor-specific HLA-antibody (DSA) production in 53 kidney transplant patients Although early development of DSA was not associated with Treg numbers, at 12 months after kidney transplant DSA-negative patients had higher number of peripheral blood Treg
The mechanisms for which higher peripheral blood Tregs help prevention of allograft rejection and mainten-ance of transplant tolermainten-ance meet the same concept of peripheral regulation in autoimmune reaction [18, 29–
32] On a cellular basis, Tregs utilize four modes of ac-tion in peripheral regulaac-tion including [29–32]; i) secre-tion or generasecre-tion of inhibitory cytokines (e.g., 10,
IL-35, TGF-β and adenosine); ii) direct killing of targets through Granzyme A/B and perforin-dependent cytoly-sis; iii) IL-2 consumption through high IL-2R expression which leads to cytokine-mediated deprivation and
Fig 3 Plasma cytokines were measured by multiplex cytokine immunoassay Box plots exhibited plasma levels of anti-inflammatory cytokines
IL-10 and TGF- β1, and pro-inflammatory cytokines GM-CSF, IFN-γ, IL-2, IL-4, IL-5, IL-12, IL-13 and TNF-α (n = 26; 14 desflurane, 12 sevoflurane) IL-10 showed an increased trend over 24-h period in patients receiving desflurane anesthesia Des, desflurane; Sevo, sevoflurane
Fig 4 Matched-pair data analysis of Tregs and IL-10 ( n = 26; 14 desflurane, 12 sevoflurane) Fold change was calculated by Tregs (or IL-10) measured at 24-h divided by that of pre-exposure (0-h) in the same patient, in which fold change > 1 indicated upregulation and fold change <
1 was downregulation a Scatter plot exhibited the positive relationship between Tregs and IL-10 fold changes b Bar plots showed a higher proportion of co-increased Tregs and IL-10 immunophenotypic response in patients receiving desflurane anesthesia Des, desflurane;
Sevo, sevoflurane
Trang 8apoptosis of effector cells; and iv) direct interaction with
CTLA-4, LAG-3 and PD1 molecules Although
accumu-lating evidence would favor contact-dependent
mecha-nisms over non-contact/secretory component alone,
these different mechanisms should work in concert to
control various immune effector cells and regulate
dif-ferent inflammatory settings [29–32] Given that breadth
of regulatory function on autoimmunity and
self-tolerance, changes in peripheral blood Tregs in kidney
transplant recipients may shift the balance between
allo-graft rejection and transplant tolerance
According to these lines of evidence, the increment of
Tregs and IL-10 (Figs.2,3 and4) after exposure to
des-flurane anesthesia should be beneficial to graft outcomes
in LDKT recipients In fact, several drugs routinely used
in general anesthesia (besides volatile anesthetic agents)
have immunomodulatory properties [25, 26] It is
pos-sible that some of them have positive effects on Tregs
Synergistic effects of multiple Treg-modulated agents
may provide a better transplant outcome Understanding
how anesthetic agents exhibit varied effects on the
im-mune system, particularly on Tregs, is important for
fu-ture development of perioperative medicine in kidney
transplantation
This study was associated with several limitations
First, clinical outcomes, such as short-term and
long-term graft survival, that were associated with Treg
immunomodulation of desflurane anesthesia were not
investigated Graft survival is influenced by various
fac-tors (such as adequacy and toxicity of
immunosuppres-sive drugs, presence of donor-specific antigen, PRA
levels, numbers of HLA mismatch) These factors,
to-gether with Treg immunomodulation of desflurane,
should be taken into account in future studies Secondly,
plasma cytokine levels were measured in 26 out of 40
patients (2/3 of total population in this study) due to the
limited budget A non-significant difference of cytokines
between intervention groups may be due to a lack of
statistical power, but at least, the upward trend of
plasma IL-10 was observed, given the supportive
evi-dence that desflurane anesthesia induced peripheral
blood Tregs with potential IL-10 production Third, the
mechanisms of action (MoA) that drive desflurane-Treg
immunomodulation were not defined and not the focus
of this study Further studies to characterize receptors
and downstream signaling pathways that are responsible
for desflurane-Treg effects would give some insight into
a new MoA class of volatile anesthetic agent or a new
biological process that facilitates transplant tolerance in
LDKT recipients
Conclusion
In summary, desflurane had the advantage over
sevoflur-ane as the inhalation sevoflur-anesthetic in LDKT patients
regarding the increment of peripheral blood Tregs Fur-ther research focused on clinical outcomes and pharma-cological actions of desflurane on Treg immunomodulation has translational potential, which could eventually benefit LDKT recipients
Supplementary information
Supplementary information accompanies this paper at https://doi.org/10 1186/s12871-020-01130-7
Additional file 1: Table S1 Effects of sevoflurane and desflurane anesthesia on plasma cytokine levels of LDKT patients.
Abbreviations
ADPKD: Autosomal dominant polycystic kidney disease; BMI: Body mass index; ESRD: End-stage renal disease; HLA: Human leukocyte antigen; LDKT: Living donor kidney transplantation; MoA: Mechanisms of action; PRA: Panel reactive antibodies; Th1: T helper 1; Th2: T helper 2;
Tregs: Regulatory T cells
Acknowledgments
We are grateful to all staff of the Ramathibodi Kidney Transplant Project SC was financially supported by Faculty Staff Development Program of Faculty
of Medicine Ramathibodi Hospital, Mahidol University, for his research activities.
Authors ’ contributions
AC and SC initiated the conception AC, NOA, GG, WI, VS, SC developed the design SP performed patient recruitment, randomization, and allocation AC and WI performed anesthesia intervention NUA, GG, VS provided medical care and surgical operation NP, SS, NK, NOA, SH, SC performed Treg enumeration and cytokine measurement AC, SP, SC analyzed data, prepared figures and tables AC and SP wrote the manuscript NP, SS, NK, NOA, GG, NUA, SH, WI, VS, SC revised the manuscript All authors read and approved the final version to be published.
Funding This study was supported by Talent Management Program of Mahidol University, Thailand (TM:CP131 to AC) The funder had no role in study design, collection, and analysis of data and the decision to publish the manuscript.
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics approval and consent to participate This study was approved by the Ethical Clearance Committee on Human Rights Related to Research Involving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University (protocol ID 045823) and the protocol was registered to ClinicalTrials.gov (identifier NCT02559297) All patients provided their written informed consents to participate in this study.
Consent for publication Not applicable.
Competing interests The authors declare no conflict of interests.
Author details
1 Department of Anesthesiology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand 2 Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand 3 Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
10400, Thailand 4 Vascular and Transplantation Unit, Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
10400, Thailand 5 Division of Infectious Disease, Department of Pediatrics,
Trang 9Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
10400, Thailand 6 Division of Hematology and Oncology, Department of
Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University,
Bangkok 10400, Thailand.7Division of Nephrology, Department of Medicine,
Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
10400, Thailand 8 Department of Clinical Epidemiology and Biostatistics,
Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok
10400, Thailand.
Received: 20 June 2020 Accepted: 20 August 2020
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